Pyrimidine derivatives



l atentecl June 15, 1948 PYRIMIDINE DERIVATIVES Francis H enry Swinden Curd, Manchester, Eng"- land, Margaret Isabel Hall (ne Davis), Ann'an,

Scotland, and Edmund Cecil Owen, Francis Leslie Rose, and George Alfred Peter Tuey, Manchester, England, assignors to Imperial Chemical Industries Limited, a corporation of Great Britain No Drawing. Application August 28, 1945, Serial No. 613,218. In Great Britain September 25,

Claims. (01. 260-251 This invention relates to the manufacture of new pyrimidine compounds which are useful as chemotherapeutic agents and as intermediates therefor. Many of them are useful as parasiticidal agents, especiall against the malaria parasites.

The said new compounds are pyrimidine derivatives of the formulawherein X is hydrogen or a hydrocarbon radical, Y is hydrogen or a neutral substituent, such, for example, as a hydrocarbon radical, an alkoxy or aryloxy or alkylmercapto group, or a cyano or nitro group, and also X and Y may be joined together to form an alkylene chain, and of the groups Z and Z, one is an arylamino group which may be substituted or unsubstituted but must be free from strongly acidic groups of the kind here inafter described, and the other is a radical of the form--NR"ANRR wherein R is hydrogen or an alkyl or simply substituted alkyl group, for example, an alkoxyalkyl or dialkylaminoalkyl group, A is a linking group, which is aliphatic or alicyclic or aliphatic-carbocyclic and may be substituted, for example, by hydrocarbon radicals, alkoxy groups or dialkylaminoalkyl groups, and, where A or part of A is an aliphatic chain it may be interrupted by oxygen, nitrogen or sulphur atoms and N'RR' is a substituted amino group such as acylamino, alkylamino or dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group.

We make the said new compounds by a process comprising the interaction of an arylamine optionally substituted in the manner indicated with an appropriate pyrimidine derivative bearing in the 2- or 4-position the groupNR-A-NRR, in the 5- and 6-positions the groups Y and X respectively and in the 4- or 2-position a halogen atom.

The reaction is conveniently brought about by heating the reagents together, optionally in the presence of a solvent or diluent. The reagents need not be present in the exact stoichiometric proportions; in fact it is sometimes convenient to use an excess of the arylamine as-a solvent or diluent. If desired, the arylamine may be used in the form of a salt such as the hydrochloride or acetate, or the pyrimidine derivative may be used in the form of a salt preferably with one equivalent of acid, for example, the monohydrochloride. It is particularly convenient to work in an aqueous medium, using one molecular proportion each of the halogeno-pyrimidine and the arylamine and one molecular proportion or a slight excess thereover of a mineral acid.

Th arylamines to be used as starting materials and hence also the arylamino groups introduced into the molecule may be unsubstituted or may bear one or more substituents provided that they are free from strongly acidic groups. The term strongly acidic groups as used herein includes sulphonic acid, sulphuric ester (i. e., sulphato) carboxylic acid, phosphonic acid, arsonic acid and like acid groups; it does not include the relatively feebly acidic groups such as phenolic hydroxyl and mercapto groups. These latter groups and likewise halogen atoms, nitro groups, hydro-carbon radicals (which themselves may optionally bear substituents and which may be attached to the arylamino group directly or indirectly, as for instance through an oxygen, nitrogen or sulphur atom or a carbonyl group), cyano groups and esterified carboxyl groups are examples of substituents which may be present in the arylamino group.

Then as examples of particular arylamines suitable to be used as starting materials there may be mentioned aniline, o, mand p-chloroanilines, 0- and p-methoxyanilines, o, mand p-toluidines, oand p-bromoanilines, p-methylmercaptoaniline, 2:4-, 3:4- and 2:5-dichloroanilines, '3 4-dimethylaniline, 2-methyl-4-chloroaniline, 3-chlorol-methylaniline, p-dimethylaminoaniline, p-nitroaniline, p-mercaptoaniline, p hydroxyaniline, p dimethylaminosulphonylaniline, p-cyanoaniline, p-ethoxyaniline, p-carbomethoxyaniline, p-n-butylaniline, p-phenylaniline, ozand p-naphthylamines, i-chloro-nL-naphthylamine, G-bromo-p-naphthylamine, G-methoxy-B-naphthylamine and G-hydrOXy-p-naphthylamine.

'The 2- or -halogenopyrimidine compounds used as starting materials may be made by reaction of a halogenating agent such as a phosphorus pentahalide" or oxyhalide with the corresponding hydroxypyrimidine compounds, our

copending application Serial No. 613,217 of even date herewith.

The new 2- or 4-arylaminopyrimidines bearing a basic substituent in the 4- or 2-position and optionally bearing other substituents in the and 6-positions obtained in accordance with this invention are strongly basic colourless or pale yellow viscous oils or crystalline solids. When the bases are oils, the picrates, which are crystalline, may be used for purposes of characterisation. The bases form colourless salts withQmineraland organic acids. The salts with mineral acids such as hydrogen halides, sulphuric and phosphQ ic acids or with lower organic acids 'such as acetic, lactic, tartaric and lower alkanesulphonic acids (e. g., methanesulphom'c acid) arewater-soluble. The salts with acids of higher molecular weight such as methylene bis-2 3-hydroxynaphthoic acid and methylene bis-salicyclic acid are more sparingly soluble in water.

The following examples illustrate, but do not limit, the invention. The .parts are by weight.

Example 1 5.2 parts of 4-chloro-2-Y+diethylaminopropylamino-6-methylpyrimidine, 3.3.parts of p-chloroanilin hydrochloride and 7.68 parts of p-chloroaniline are mixed and heated to l70-175 C. for 2 hours. The mixture is cooled and stirred with 50 parts of benzene to dissolve out unchanged p-chloroaniline and the undissolved residue is filtered off and dried. It is purified by dissolving in 40 parts of watercontainingfllpart of acetic acid and 1 part of sodium acetate, heating the solution with decolourising carbon and filtering hot. The dihydrochloride is then salted out from the filtrate by addition of sodium chloride, filtered off and washed with a little cold water. The 2 -ydiethylaminopropylamino 4 p-chloroanilino-G-methylpyrimidine dihydrochloride thus obtained is finally purified by crystallisation from methanol and then has M. P. 2682'l0 C. 2-1 diethylaminopropylamino '7 4 -zpchloroanilino -6- methylpyrimidine also forms a monohydrochloride-monopicrate, M. P. 236-238 C. and dipicrate, M. P. 212214 C.

By working in a similar manner, using a mixture of the arylamine and arylamine hydrochloride but starting from, other appropriate arylamines and halogenopyrimidines the following further compounds are obtained.

Example 2 2-c-diethylaminoethylamino.- 4 pchloroanilino-G-methylpyrimidine dihydrochloride, M. P. 266263 C.

Example 3 2 [3 diethylaminoethylamino-l-p-methylanilino-fi-methylpyrimidlne dihydrochloride, M. P. 236-238 C.

Example 4 Example 5 2-5-diethylaminoethylamino 4 p methoxyanilino 6 methylpyrimidine dihydrochloride, M. P. 216218 C.; the dipicrate has M. P. 180 C.

Example 6 dipicrate has methylpyrimidine dihydro- 2-c-diethylaminoethyla'mino 4 (3' :4 -di chloroanilino) -6-methylpyrimidine dihydrochloride,

.ani1in'o-5-ethyl 6 methylpyrimidine M. P. 260-261 0.; the dipicrate has M. 1 218-219 0.

the monohydrochloride monopicrate (made by adding picric acid in alcohol to a solution of the dihydrochloride in alcohol) has M. P. 228 C.

Example 8 2-5-diethylaminoethylamino-4-p-nitroanilinofi-methylpyrimidine dihydrochloride, M. P.

Example 9 '2-p-diethylaminoethylamino 4 pcyanoanilino-fi-methylpyrimidine dihydrochloride, M. P.

Example 10 5.5 arts or 4-chloro-2-6-diethylaminobutylamino-G-methylpyrimidine, 7.68 parts of pchloroaniline and 3.3 parts of p-chloroaniline hydrochloride are mixed and heated at -l60 C. for 2 hours. The reaction mixture is extracted several times with hot benzene. The undissolved residue is then dissolved in water, acetic acid and sodium acetate added and thesolution is extracted twice with benzene. The aqueous'layer is separated, stirred with decolourising carbon and filtered. Caustic soda is added to the filtrate and the base, which is precipitated as an oil, is extracted with chloroform. The chloroform extract is dried over sodium sulphate and the chloroform is distilled off. The oil remainin is lino-fi-methylpyrimidine which is converted into its dihydrochloride with hydrochloric acid in aqueous methanol. Recrystallised from aqueous methanol the dihydrochloride has M. P. 197- 198 C. The corresponding dipicrate crystallises from ,B-ethoxyethanol: M. P. 226-227 C.

Example 11 4-p-chloroanilino-Emethylpyrirriidihe dihydrochloride of M. P. 270 C.

By working in'a similar manner. to that; described in Example 11, but using other appropriate starting materials, the following further compounds are obtained.

, v Example 12 2 -'y dibutylaminopropylamino 4 -chl oroanilino 6 'methylpyrimidine dihydrochloride, M. P, 171-1'73 C.; the dipicrate has M. P. 220-222 C.

Example 13 '2-' piperidinopropylamino-4-p ch1oroanilinofi-methylpyrimidine' dihydrochloride, M. 1?. 277- Example 14 2 -"ydiethylaminopropylaminop g chlorodillydr0- chloride, M. P. 245-246 C.

2 -6- diethylaminobutylamino-4-p chloroanilino-fi-methylpyrimidine dihydrochloride, M. P. 301303 C.

Example 16 2 -'ydibutylaminopropylamino 4 p chloroanilino 5 ethyl-fi-methylpyrimidine dihydrochloride, M. P. 215-216 C.

Example 17 12.1 parts of 2-chloro-4-;8-diethylaminoethylamino-G-methylpyrimidine and 12.5 parts of p-chloroaniline are heated together at 150-160 C. for 6 hours. The reaction mixture is dissolved in hot dilute hydrochloric acid and the solution is filtered, cooled and basified with caustic soda solution. The base, which is liberated as an oil, is extracted with chloroform, the solution is dried over anhydrous potassium carbonate and the chloroform is distilled oiT. 2-p-chloroanilino-4- fl-diethylaminoethylamino-6 methylpyrimidine remains. It is distilled in vacuo and the fraction of B. P. 204-208 C./0.2 mm. is collected. The picrate, made by interaction with picric acid in ethanol and crystallised from ,B-ethoxyethanol, has M. P. 218-219 C.

The base is converted to the hydrochloride by dissolving in 2-norma1 hydrochloric acid and evaporating the solution to dryness. After drying, the residue is crystallised from alcohol. There is thus obtained 2-p-chloroanilino-4- diethylaminoethylamino-S-methylpyrimidine dihydrochloride, M. P. 270-271 C.

By working in a similar way to that just described, but using other appropriate arylamines as starting materials there are obtained the following further 2-arylamino-4-B-diethylaminoethylamino-6-methylpyrimidines in the form of their dihydrochlorides.

Example 18 2-p-methoXyanilino-4 e diethylaminoethylamino-6-methylpyrimidine dihydrochloride, M. P. 231-232 C.

Example 19 2-p-methylanilino-4-e diethylaminoethylamino-6-methylpyrimidine dihydrochloride, M. P. 216-218 C.

Example 20 2-p-methylmercaptoanilino-4-fi-diethylaminoethylamino-6-methylpyrimidine dihydrochloride, M. P. 232-234 C.

Example 21 2-fl-naphthylamino- 4 B diethylaminoethylamino-G-methylpyrimidine dihydrochloride, M. P. 252-254 C. (decomp.).

Example 22 2-(6'-bromo-2'-naphthylamino) -4- o diethylaminoethylamino-6 methylpyrimidine dihydrochloride, M. P. 290 C. (decomp.).

Example 23 2-(6'-meth0xy-2'-naphthylamino) 4 [3 diethylaminoethylamino-G-methylpyrimidine dihydrochloride, M. P. 228-230 C. (decomp).

Example 24 v 2-o-chloroanilino-4- ,8 diethylaminoethylamino-fi-methylpyrimidine dihydrochloride, M. P. 25.1-253 C.

Example 25 2-anilino 4 p diethylaminoethylainino 6 methylpyrimidine dihydrochloride, M. P. 264 C. (decomp.)

Example 26 Z-o-methoxyaniliho- 4 B diethylaminoethylamino-fi-methylpyrimidine dihydrochloride, M. P. 272-273 C.

Example 27 2-o-methylanilino-4-o diethylaminoethylamino-fi-methylpyrimidine dihydrochloride, M. P. 237-238 C.

Example 28 2-m-methylanilino-4-p-diethylaminoethylamino-6-methy1-pyrimidine dihydrochloride, M, P. 272-274 C.

Example 29 2-p-ethoxyani1ino-4-fldiethylaminoethylamino-fi-methylpyrimidine dihydrochloride, M. P. 211-213 C.

Example'30 2-a-naphthylamino- 4 [3 diethylaminoethylamino-d-methylpyrimidine dihydrochloride, M. P. 275276 C. (decomn).

Example 31 2-(4'-ch1oro-1'-naphthylamino) -4- B diethylaminoethylamino-6-methylpyrimidine dihydrochloride, P. 294-295 0.

Example 32 filtered off and dried. It may be purified by crystallisation from a mixture of ethyl alcohol and ethyl acetate and then has M. P. 250-252 C.

By working in a similar manner with other appropriate starting materials, using in each case equimolecular proportions of the arylamine, chloropyrimidine and hydrochloric acid, there are obtained the following further compounds.

2- -dibutylaminopropylamino-4-p bromoanilino-6-methylpyrimidine dihydrochloride, M. P. -161 C.

Example 36 2-' -dibutylaminopropylamino-4-p chloroanilino-fi-methylpyrimidine dihydrochloride, M. P. 171-173 C.

Example 37 2 y diethylaminopropylamino-4-p-chloroanilino 6 methylpyrimidine dihydrochloride, M. P. 268 270 C.

Example. 38 *2 .--v piperidinopropylamino-4 m-nitroani1inofi-methylpyr-imidine *dihydrochloride, P1. .262- 264 C'.

Example 39 '2 Y piperidinopropylamino b(6'-bromo-2- naphthylamino) -'6 methylpyrimidine dihydrochloride, M. P. 288-289 C.

Example 40 2 /piperidinopropylamino-4-pnitroanilino G-methylpyrimidine dihydrochloride, M. P. 277 2'79" 0.; the base has M. P. 174-175 '0.

Example 41 2- y 'dibutylaminopropylamino-4-p-cyanoanilino 6 methylpyrimidine dihydrochloride, M. P. 224-226 C.

Example 42 2 (N-methyl-N-c-diethylaminoethy1-amino) 4 p-chloranilino-S-methylpyrimidihe dihydrochloride, M. P. 244-'-246 C.; the base has M. P. 83-85 C.

Example 43 2 Y diethylaminopropylamino-4-p-cyanoanilino-G-methylpyrimidine dihydrochloride, M. P.;274-275 C.

Example 44 2 Q y-piperidinopropylamino-4-p cyanoanilino- 6-methylpyrimidine dihydrochloride, M. P. 230- 282" C.

Example 45 Example 46 2 p hydroxyanilino-4-c-diethylaminoethyl amino-S-methylpyrimidine dihydrochloride, M- P. 2"l'O-272 C.

1 Example 47 I 2 7 diethylaminopropylamino-4-p-hydroxyanilino-fi-methylpyrimidine dihydrochloride, M..- .P. 269-271 C. (decomp.).

Example 48 V 2 7 dibutylaminopropylamino-4-p-hydroxy-- anilino-G-methylpyrimidine dihydrochloride, M. P. 120-122 C.

' Example 49 A mixture of 6.4 parts of 2-7-diethylaminopropylamino 4. chloro-fi-methylpyrimidine,

3.45 parts of p-nitroaniline, 40 parts of water,

parts of acetone and 2.5 parts of concentrated. hydrochloric acid are refluxed for 1. hour. On. cooling 2 7 diethylaminopropylamino-4-p-nitroanilino. G-methylpyrimidine dihydrochloridecrystallisesuout and is filtered off, dried and recrystallised from alcohol to which a .smalli.pro-- propylamino-6methylpyrimidine portion of water has been added. It then forms yellowish blunt needleS- OfM. P. 273-275 C.

Example '50 3.2 parts of 2-chloro-4-'y-diethylaminopropylamino-6-methylpyrimidine, 1.6 parts of p-chloroaniline, 1.2 parts of -concentrated hydrochloric acid, 15 parts of water and 5 parts of acetone are refluxed together for 1 hour. The .clear solution so obtained is diluted with-water .and made alkaline with caustic soda. The base which is liberated is extracted with chloroform, the extract is dried and the chloroform is distilled off. The residue is distilled under diminished pressure, whereby 2 p-chloroanilino-4-Y-diethy1aminopropylamino-G-methylpyrimidine is obtained in the form of an-oil of B. P.-210218? ("l/0 .15 mm. It forms a dipicrate of M. P. 2252-226" C. anda dihydrochloride of M. P. -252-254= C.

By working in a similar manner but using other appropriate starting materials there are obtained the following further compounds.

Example 51 2 p-dimethylaminoanilinoi-y-diethylaminopropylaminoefi-methylpyrimidine; the trihydrobromide, made by dissolving the base in hydrobromic acid and adding aceticacid, has M. P. 258-258 C.

Example 52 2 ,8-naphthylamino-4-7-diethylaminopropylamino-G-methylpyrirnidine dihydrochloride, M; P. 259-260 C. (dcomp). 7

Example 53 2 (2 methyl-4'-'chloroani1ino)-4-Y-diethy1- aminopropylamino-6-methylpyrimidine dihydrochloride, M. P. --152 C.

Example 54 2 o chloroanilino-4rY-diethy1aminopropy1 amino-6-methylpyrimidine dihydrochloride, M. P. 238239 C. 7

Example 55 2 m chloroanilino-l-v-diethylaminopropyh amino-fi-methylpyrimidine dihydrochloride, M. P. 215-21'7 C.

Example 56 2 (2z4' dichloroanilino) -4-Y-diethy1aminopropylamino G-methylpyrimidine dihydrochlo- Example 58 2- (2' :5 -dich1oroani1ino-) -4-ydiethylamino- 'dihydrochloride, M. P. 248-250 C.; the base has P. 98-100 C. (decomp.).

2 (3-chloro-4=f-methylanilino) -4-'ydiethyl- ,aminopropylamino-6 methylpyrimidine dihydrochloride, M. P. 230-232 C.

Example 62 2- (3 '-dimethylanilin0) -4-- diethylaminopropylamino -6- methylpyrimidine dihydrochloride, M. P. 306308 C.

Example 63 2- (3 :5-dibromoanilino) -4-'ydiethylaminopropylamino -6- methylpyrimidine dlhydrochloride, M. P. 264-266 C.

Example 64 2 -pbromoanilino -4'ydiethylaminopropylaminopropylamino-G-methylpyrimidine dihydrochloride, M. P. 255-257 C.

Example 65 2 -pbutylanilino -4-'ydiethylaminopropylamino 6 methylpyrimidine dihydrochloride, M. P. 188-190 C.

Example 66 Z-p-carbomethoxyanilino -4-'ydiethylaminopropylamino -6- methylpyrimidine dihydrochloride, M. P. 263-265 C.

Example 67 2 -pphenylanilino 4-'ydiethylaminoethylamino 6 methylpyrimidine dihydrochloride, M. P. 244-246 C.

Example 68 2-p-nitroani1ino 4 'y diethylaminopropylamino 6 methylpyrimidine dihydro chloride, M. P. 226-232 C.

Example 69 2 -pcyanoanilino -4-'ydiethylaminopropylamino 6 methylpyrimidine dihydrochloride, M. P. 249-251 C.

Example 70 2 -pchloroanilino 4-'y diethylaminopropylaminopyrimidine dihydrochloride, M. P. 208- 210 C.

Example 71 14.2 parts of 2-fi-diethylamino-a-methylbutylamino-4-chloro-6-methylpyrimidine, 6.35 parts of p-chloroaniline, 50 parts of water and 4.4 parts of concentrated hydrochloric acid are refluxed together for 2 hours. The resulting clear solution is made alkaline with caustic soda and the oil which is precipitated is separated oil and extracted several times with chloroform. The combined chloroform extracts are shaken several times with 5% acetic acid, and'the acetic acid extracts are combined and made alkaline with caustic soda. The precipitate which forms is dissolved in chloroform, the chloroform solution is dried over potassium carbonate and the chloroform is distilled oif. The remaining oil is then distilled in vacuo, whereby z-fi-diethylamino-amethylbutylamino -4-pchloroanilino-G-methylpyrimidine is obtained as a colourless oil, B. P. 220-223 C./O.l5 mm. It can readily 'be converted into the dihydrobromide by solution in dilute hydrobromic acid and evaporation to dryness in vacuo; recrystallised from a mixture of ethanol and ethyl acetate the dihydrobromide forms colourless fiat prisms of M. P. 200-201 C. The dipicrate crystallises from a mixture of 10 ethanol and p-ethoxyethanol in clusters of small yellow needles, M. P. 189'-190'C.

By working in the manner just described but using as starting materials 2-chl0r0-4-6-diethy1- amino-a-methylbutylamino -6- methylpyrimidine and various arylamines, the following further compounds are obtained.

Example 72 2-p-chloroanilinoi-a-diethylamino-a-n1ethylbutylamino-G-methylpyrimidine, B. P. 204-206 C./0.15 mm.; the dipicrate has M. P. 168-170 0.

Example 73 2-m-chloroanilino-4-6-diethylamino-a-methylbutylamino-6-methylpyrimidine B. P. 235-237 C./1.5 mm.; the dihydrochloride has M. P. 205- 207 C.

Example 75 2-p-bromoanilino-4-6-diethylamino -amethyl butyl-amlno-G-methylpyrimidine, B. P. 240-242 C./ 1.0 mm.; the dihydrochloride has M. P. 244 C.

Example 76 2- (3' :4'-dichloroanilino) -4-6- diethylaminoa-methylbutylamino-6-methylpyrimidine, B. P. 242-246 C./1.0 mm.; the dihydrochloride has M. P. 257 C.

Example 77 U 2 p methoxyanilino -4 6 diethylamino-amethylbutyl-amino-G-methylpyrimidine,' B. P. 227-231 C./-1.0 mm.; the dihydrochloride has M. P. 245 C.

Example 78 2-o-methoxyanilino-4-6-diethylamino-a-meth-. yl-loutylamino-fi-methylpyrimidine, B. P. 229- 231 C./1.8 mm.; the dihydrochloride has M. P. 225 227? C.

By working in the manner described in Example 71, but using other appropriate starting materials the following additional compounds are obtained.

Example 79 2- 3 diethylaminoethylamino 4-p-chloroanilino-6-methylpyrimidine, B. P. 193-200 C./0.65 mm. After crystallisation from petroleum ether it has 97 C. The dipicrate has M. P. 227-228 C.

Example 80 2-5 diethylaminoethylamino e-p-methylanilino-fi-methylpyrimidine, M. P. 66-68 C.; the dipicrate has M. P. 191-193 C.

Example 81 2-p -diethylaminoethylamino-4-p-nitroanilino- G-methylpyrimidine, M. P. 161-162 C.

Example 82 2-6-diethylamino-a-methylbutyl amino 4-p cyanoanilino-G-methylpyrimidine, B. P. 233-239 C./0.15 mm. The dipicrate has M. P. 199-200 C. and the dihydrobromide M. P, 216-220 C.

Example 83 2-6-diethylamino-a'-methylbutyl amino 4-pnitroanilino-6-methylpyrimidine; the dipicrate has M. P. 173-176 C. and the dihydrochloride M. P. 114-118 C.

g Emampleidel' 2-.6-diethylamino-a.=me,thylbutyl arnino 4- s,'-

1 bromoirzfnaphthylamino) e, G-methylpyrimidine;

the dipicrate has M. P. 238 241? G. and the dihydrochloride M. P; 2602-262". C.

Example 85 ZL-y-dibutylaminopropylaminoe l (2' :4} -.dichloroanili'no). demethylpyrimidine, B. P, 220f-222 C;/';12imm.; thedipicrate hasM. P. 226- 2 2' 7 vC.

Example 86. 2-'y-dibutylagminopropylaminor4 (3 vii-dichloroanilijnol-fiemethylpyrimidine the dipicrate has Example 90 2- y-(,6'-diethylaminoethoxy) propylaminol- 'nitroanilino-6-rnethylpyrimidine;. P. 10 8 Example 91 2. .v-butylaminopropylamino 4-p-n-itroanilino- 6-:methylpyrimidine, M-. P. 141'-143? C.

Example 92 2-'y-dimethylaminopropylamino -p-nitroanilino-6-methylpyrimidine,- P. 184 C.

Exam le 93 2- -(p -diethylarninoethoxy) propylaminor le p-chloroanilino 6methylpyrimidine. The'base is an oil; the dipicrate has M. P. 148-150 C. and the dihydrochloride M.- P. 1'l8-180 C.

Exa e 9 2-7- (N-methyl-Nw -diethylaminoethyl amino) -propylamino l-1: -chloroanilino G-methylpyrimidine. The trihydrochloride has M. P. 239 240 C.

Example95 7.8 parts of 2-'y-dibutylaminopropylamino-4=- chIoro-GPmethyIpyrimidine, 4.1 parts of m-chloroanil-ine. hydrochloride. 25 parts of water and 0.25 part .of concentrated hydrochloric acidare refluxed together for 1 hour. [The resulting solution is made alkaline withcaustic soda and the oil which is precipitated; is separated off and extracted with 5% acetic acid. The acetic acid extract ismadealk'alinewith sodium hydroxide and theoil' which is again. precipitated .is extracted with chloroform. The chloroform solution is dried and the chloroform is distilled off. The

ethyl acetate.

of equimolecular proportions residue is 2-' -dibutylaminopropylamino4-m-.

by stirring with 2-normal hydrochloric acid. The

crystals are filtered off, dried and recrystallised firstfrom, a mixture of .ethyl acetate and. methanol-and then from'a mixture of butanol and It then forms colourless thick prisms, M. P. 221-223 C.

Example 96 Example 97 7.1 parts of 2-*y-diethylaminopropylaminolchloro-5-ethyl-fi-m'ethylpyrimidine, 3 parts of p-cyanoaniline, 2.5 parts of concentrated hydrochloric acid and 25 parts of water are refluxed together for 1 hour. The solution is cooled and made alkaline with sodium hydroxide. The base which: is precipitated is filtered off and redissolved in 5%iaqueous acetic acid. The solution isagain made alkaline with sodium hydroxide and the base is filtered off and dissolved in chloroform. The solution is dried and the chloroform is distilledoff. The residueis recrystallised from aque' ous'. ethanol and then from benzene. There is thus obtained '2-'y-diethylaminopropylamino-4- p-cyanoanilino-5-ethyl-fi-methylpyrimidine of M. P. 151-152 C.

Example .98

By working in a similar manner but starting from 2-y-dibutylaminopropylamino-4-chloro-6- methylpyrimidine and p-nitroaniline, there is obtained 2-?-dibutylaminoprOpylamino--p-nitroanilino-fi-methylpyrim idine of M. P. 118-119 C. The dihydrochloride has M. P. 224-225 C.

Example 99 21.35 parts of. 2-chloro-4-Y-diethylaminopropylamino-5enitro-G-methylpyrimidine hydrochloride (M. P. 157-158 C. made by interaction of y-diethylaminopropylamin and 2:4-dichloro-5-nitro-6-methy1- pyrimidine in ethanol), 8.77 parts of p-chloroaniline and parts-of ethanol are refluxed together for 3 hours. The solid which has separatedout is filtered ofi and stirred with sodium hydroxide solution andthe base so liberated is extracted with chloroform. The chloroform is evaporated oh and the residue is extracted with 500 .parts of 5%. aqueous acetic acid. The acetic acid solution ismade alkaline with sodium hydroxide and the base which is precipitated is extracted with chloroform. The chloroform solution is dried, thechloroform is distilled off and the residue is crystallised from petroleum ether. Ther is thus obtained 2-p-ch1oroani1ino-4-Y- diethylaminopropylamino 5-nitro-6-methylpyrimidine of M. P. 94 -96 C.

Example 1 00 Byworking in the manner described in Example 99. but using as the chloro -compound 2- chloro-4-fi-diethylaminoethylamino nitro-6- methylpyrimidine hydrochloride (M. P. 220-222 C., decomp., mad b interaction 01" equimolecular proportions of 13-diethylaminoethylamino and 2:4 dichloro 5 nitro 6 methylpyrimidine in ethanol), there is obtained 2-p-chloroani1ino-4- pj diethylaminoethylamino-5-nitro-6-methylpyrimidine of M. P. 95-97 C.

Whereas the above description and examples illustrate many widely varied embodiments of the invention it will be apparent to one skilled in the art that many other embodiments and variations may be devised without departing from the spirit and scope thereof and accordingly it is to be understood that the invention is not in any way limited except as defined in the following claims.

In the claims below, the expression strongly acidic groups refers to radicals commonly recognized as ionizable, salt forming, acid radicals.

We claim:

1. The process of producing a pyrimidine compound having chemotherapeutic properties, which comprises reacting an aromatic amine devoid of strongl acidic groups with a pyrimidine compound bearing a halogen atom in one of the positions 2 and 4 and a diamine radical in the other of said two positions, said diamine radical having the form NH-A-NRR, wherein NRR' is a strongly basic radical selected from the group consisting of primary, secondary and tertiary amine radicals and heterocyclic nitrogenous base radicals, while A is an organic radical linking the two N-atoms of the diamine and interposing therebetween at least two aliphatic carbon atoms.

2. The process of producing a pyrimidine compound having chemotherapeutic properties, which comprises reacting an aromatic amine as hereinbelow defined with a pyrimidine compound of the general formula R N=C-GH;

N-aIk-NH-o 111 R II\|T-(1C1 wherein alk designates an alkylene radical which interposes at least 2 and not more than 6 carbon wherein alk designates an alkylene radical which interposes at least 2 and not more than 6 carbon atoms between the two N-atoms, R is a member selected from the group consisting of hydrogen and alkyl, while R designates an alkyl radical; said'aromatic amine being a primary aromatic amine of the benzene series which is devoid of strongly acidic groups.

4. A process as in claim 1, wherein reaction is efiected by heating the aromatic amine and the pyrimidine compound in an aqueous medium, at

reflux temperature, in the presence of hydrochloric acid.

5. A process as in claim 4, wherein the resulting compound is isolated in the form of its dihydrochloride.

FRANCIS HENRY SWIN'DEN CURD. MARGARET ISABEL HALL (NEE DAVIS). EDMUND CECIL OWEN.

FRANCIS LESLIE ROSE.

GEORGE ALFRED PETER TUEY.

REFERENCES CITED The following references are of record in the file of this patent:

Jour. Amer. Chem. 800., vol. 67 (1945); pp. 1159-61 and 735-38.

Amer. Chem. Jour., vol. 33 (1905), pp. 439 and 449; and vol. 40 (1908), pp. 143-146.

Certificate of Correction Patent No. 2,443,305.

FRANCIS HENRY SWINDEN OURD ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column 2, line 50, after the word and comma compounds, insert see; column 14, line 6, for acid read acidic; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Oflice.

Signed andsealed this 31st day of August, A. D. 1948.

THOMAS F. MURPHY,

Assistant Oommz'ssz'oner of Patents.

June 15, 1948. 

